Program Description/Abstract Lineage commitment and maintenance are fundamental processes in a variety of biological systems. In the immune system, dysregulated T cell responses are the cause of many allergic and inflammatory disorders. TH17 cells play a key pathogenic role in Multiple sclerosis (MS) and its murine model, experimental autoimmune encephalomyelitis (EAE). A unique feature of TH17 cells is their inherent plasticity that endows mature effector TH17 cells with characteristics of other T cell subsets especially TH1 cells, but how this process is controlled and its functional significance remain elusive. Coordination of T cell metabolic programs with cell fate decisions is a fundamental process in adaptive immunity, but how metabolic pathways intersect with immune signals in T cell fate decisions and autoimmune dysregulation is poorly defined. In particular, the function of metabolic programs in effector T cell plasticity and pathogenicity remains essentially unexplored. Our preliminary results identified the key roles of mTORC1 and metabolic pathways in the programming of pathogenic responses in effector TH17 cells. Loss of mTORC1 activity in TH17 cells via the Il17aCre deletion system abrogated neuroinflammation and tissue damage in EAE. Mechanistically, mTORC1 inhibition impaired the ability of TH17 cells to transition into T-bethi IFN?-expressing terminally differentiated cells, associated with altered transcriptional responses and metabolic activities. Unexpectedly, using cutting-edge ATAC-Seq and single cell RNA-Seq technologies, we found that inhibition of mTORC1 induced TCF-1 expression and endowed TH17 cells with stem cell-like features. We hypothesize that the inherent heterogeneity of TH17 cells underlies their lineage plasticity; the balance between terminal differentiation and sustained stemness depends upon mTORC1 signaling and metabolic reprogramming, and contributes to autoimmune inflammation. Aim 1. Determine transcriptional mechanisms and developmental trajectory underlying TH17 terminal differentiation and stemness. Aim 2. Establish the signaling and metabolic mechanisms of mTORC1 in TH17 responses. Aim 3. Establish metabolic control and signaling circuits of TH17 plasticity. There has been little description of molecular pathways regulating TH17 lineage plasticity. We argue that insight into metabolic control of TH17 plasticity could establish a new paradigm of T cell fate control mechanisms, and manifest legitimate therapeutic opportunities for autoimmune diseases.